This week, researchers at the Netherlands Cancer Institute
published the results
of the NABUCCO study in scientific journal Nature Medicine. In this
publication, they show that neoadjuvant immunotherapy using a
combination of two drugs (nivolumab and ipilimumab) is a feasible
treatment for bladder cancer without harming the scheduled
resection, and shows promising results.
With this publication, bladder cancer is officially the third
cancer type - following
colorectal cancer - for which researchers at the Netherlands
Cancer Institute have proven the immense added value of this
combination of immunotherapy drugs before surgery for patients with
non-metastatic cancer. Studies involving other cancer types are
currently still running.
Decreasing risk of recurrence
This publication is an important milestone in our knowledge of
the treatment for bladder cancer (urothelial carcinoma). Patients
with this type of cancer often face a return of their illness after
surgery. Treatment with immunotherapy before surgery aims to lower
the risk of recurrence as much as possible. Immunotherapy does not
target the tumor itself, but strengthens the body's own immune
system to fight the disease.
Medical oncologist Michiel van der Heijden, research leader:
"Patients with bladder cancer at this stage have a high risk of
relapse but not many good treatment options, especially when the
cancer has spread to the lymph nodes. The results of this study can
hopefully benefit these patients' prospects."
Surgery as scheduled, and effective?
24 patients with locally advanced (stage III) operable bladder
cancer participated in the NABUCCO trial. Their cancer had not yet
spread through the bloodstream. With this trials, the researchers
tried to answer two questions. The main one: are all patients able
to receive their surgery on time after immunotherapy treatment? Or,
in other words: are we wasting valuable time by giving
immunotherapy before surgery? The researchers also wanted to know
whether this combination of neoadjuvant immunotherapy proves
effective for this particular patient group.
The results were promising. Out of the 24 participants, 23
managed to receive their surgery within the planned 12 weeks - even
patients with larger tumors. One patient had their surgery
postponed for four weeks due to the treatment's side effects. The
main research question could be answered with a "yes".
The study also showed that neoadjuvant immunotherapy is
effective in treating locally invasive bladder cancer: the majority
of tumors shrank significantly. 11 out of 24 patients (46%) even
showed an absence of tumor cells in tissue taken after surgery for
analysis by a pathologist: a pathological complete response.
Two out of 24 patients unfortunately relapsed within the year.
This percentage is lower than what can be expected at this stage of
the illness. One participant has since passed away from their
Which biomarkers make the difference?
The next important question: why do some patients have a better
response to immunotherapy than others? Which biomarkers are
involved that can help us predict a good response to the therapy?
One of the benefits of neoadjuvant immunotherapy is that it allows
for the opportunity to analyze these markers at a molecular level
at the start of the treatment (in a tissue biopsy) and after
surgery (in the resection margins removed during surgery).
The researchers looked into various known biomarkers that have
proven to predict immunotherapy resistance for other cancer types,
or (very) early stage bladder cancer. This led to the discovery
that T cell density in the tumor, that can be a biomarker
predicting the success if monotherapy with check point blockers in
patients with (very) early stage bladder cancer, do not affect the
combination therapy they researched.
Looking for the right ratio
The NABUCCO trial will continue: a follow-up study will try to
find the best balance between efficacy and safety by trying to
establish the right ratio of drugs that are used in this type of
combination therapy: ipilimumab and nivolumab.
Several large-scale trials will need to follow before the
results can be validated. Neoadjuvant immunotherapy will only be
available as treatment as part of a trial for bladder cancer as
well as other types of cancer.
The NABUCCO trial has been running since 2018, and is a
investigor-initiated study, developed by medical oncologist and
researcher Michiel van der Heijden and conducted by
physician-scientist Nick van Dijk and researcher Alberto
Gil-Jimenez, in collaboration with a multidisciplinary team of
physicians and researchers.
Nick van Dijk et al., Preoperative
ipilimumab plus nivolumab in locoregionally advanced urothelial
cancer: the NABUCCO trial. Nature Medicine 12 October 2020
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